Activation of Neuropeptide Y2 Receptor Can Inhibit Global Cerebral Ischemia-Induced Brain Injury

Neuromolecular Med. 2022 Jun;24(2):97-112. doi: 10.1007/s12017-021-08665-z. Epub 2021 May 21.

Abstract

Cardiopulmonary arrest (CA) can greatly impact a patient's life, causing long-term disability and death. Although multi-faceted treatment strategies against CA have improved survival rates, the prognosis of CA remains poor. We previously reported asphyxial cardiac arrest (ACA) can cause excessive activation of the sympathetic nervous system (SNS) in the brain, which contributes to cerebral blood flow (CBF) derangements such as hypoperfusion and, consequently, neurological deficits. Here, we report excessive activation of the SNS can cause enhanced neuropeptide Y levels. In fact, mRNA and protein levels of neuropeptide Y (NPY, a 36-amino acid neuropeptide) in the hippocampus were elevated after ACA-induced SNS activation, resulting in a reduced blood supply to the brain. Post-treatment with peptide YY3-36 (PYY3-36), a pre-synaptic NPY2 receptor agonist, after ACA inhibited NPY release and restored brain circulation. Moreover, PYY3-36 decreased neuroinflammatory cytokines, alleviated mitochondrial dysfunction, and improved neuronal survival and neurological outcomes. Overall, NPY is detrimental during/after ACA, but attenuation of NPY release via PYY3-36 affords neuroprotection. The consequences of PYY3-36 inhibit ACA-induced 1) hypoperfusion, 2) neuroinflammation, 3) mitochondrial dysfunction, 4) neuronal cell death, and 5) neurological deficits. The present study provides novel insights to further our understanding of NPY's role in ischemic brain injury.

Keywords: Cerebral blood flow; Cerebral ischemia; Neurological deficits; Neuronal cell death; Neuropeptide Y.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Brain Injuries* / etiology
  • Brain Ischemia* / complications
  • Heart Arrest* / complications
  • Heart Arrest* / metabolism
  • Neuropeptide Y / genetics
  • Neuropeptide Y / metabolism
  • Rats
  • Rats, Sprague-Dawley
  • Receptors, Neuropeptide Y / agonists
  • Receptors, Neuropeptide Y / genetics

Substances

  • Neuropeptide Y
  • Receptors, Neuropeptide Y
  • neuropeptide Y2 receptor